Cephalosporins

ABSTRACT

Cephalosporin compounds having a 3-position substituent of the formula (I) are described, 
     
         --CH.sub.2 --Y--Q                                          (I) 
    
     wherein Y is a bond or a linking group --NR 4  --Y&#39;--, --O--Y&#39;--, --S--Y&#39;-- wherein R 4  is hydrogen, various optionally substituted alkyl groups, alkenyl, alkanoyl or alkanesulphonyl, and Y&#39; is a bond or various optionally substituted alkylene groups; and Q is a benzene ring (optionally fused to a further benzene ring so forming a naphthyl group or optionally fused to a 5 or 6 membered heterocyclic aromatic group containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen and sulphur), said benzene ring being substituted by groups R 1  and R 2  which are ortho with respect to one another, wherein R 1  is hydroxy or an in vivo hydrolysable ester thereof and R 2  is hydroxy, an in vivo hydrolysable ester thereof, carboxy, sulpho, hydroxymethyl, methanesulphonamido or ureido; or Q is a group of the formula (II) or (III): ##STR1## wherein M is oxygen or a group NR 3  wherein R 3  is hydrogen or C 1-4  alkyl; ring Q being further optionally substituted. 
     The use of such compounds as antibacterial agents is described as are processes for their preparation and intermediates therefor.

This is a division of application No. 07/124,213, filed Nov. 23, 1987,now U.S. Pat. No. 5,114,933.

The present invention relates to cephalosporins and in particular tosuch compounds comprising a catechol or related group. This inventionfurther relates to processes for their preparation, to intermediates intheir preparation, to their use as therapeutic agents and topharmaceutical compositions containing them. The compounds of thisinvention are antibiotics and can be used in the treatment of anydisease that is conventionally treated with antibiotics for example inthe treatment of bacterial infection in mammals including humans. Thecompounds of this invention also have non-therapeutic uses as they canbe used in conventional manner in industry for example they can be usedas disinfectants and food preservatives. The compounds of thisinvention, however, are primarily of therapeutic interest as they show adesirable profile of activity and duration in their antibacterialeffect.

Investigation into new cephalosporin derivatives has been intense overthe past 25 years with many thousands of patents and scientific papershaving been published. A particular problem associated with thecommercially available cephalosporins is the lack of potency againststrains of Pseudomonas. The present invention provides cephalosporinderivatives having novel 3-position substituents, which derivativespossess good antibacterial activity and in particular against strains ofPseudomonas.

U.S. Pat. No. 4,278,793 discloses cephalosporins having a 3-positionsubstituent of the formula: --CH₂ Y wherein Y can be the residue of anucleophilic compound, preferably a sulphur, nitrogen or oxygennucleophilic compound. The emphasis therein is directed toheterocyclicthiomethyl compounds; however optionally substitutedarylthiomethyl compounds are specifically mentioned. GB1496757 disclosescephalosporins having a 3-position substituent of the formulas --CH₂ Ywherein Y can be the residue of a nucleophilic compound, thisspecification includes a discussion of nitrogen, carbon, oxygen andsulphur nucleophiles. Many possible values of Y are mentioned, includingarylthto, aryl lower alkylthio, aryloxy and aryl lower alkoxy. GB2148282 discloses cephalosporin compounds having a 3-positionsubstituent of the formula: --CH₂ R⁷ wherein inter alia R⁷ is optionallysubstituted aryl for example phenyl. The above specifications aretypical of many specifications that describe cephalosporins havingnucleophilic moities linked via a methylene group to the 3-position of acephalosporin. However, although there has been intense research over along period of time, there has been no teaching or suggestion of thecompounds of the present invention. These contain specific ring systemsthat are characterised by having hydroxy groups or related substituentsortho to one another. These hitherto undisclosed ring systems give riseto particularly good activity against strains of Pseudomonas. Mentionshould be made of Japanese Kokai 62-051688, published after the prioritydate of the present invention, which discloses7-(2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido-3-(3,4-dihydroxyphenyl)methyl-ceph-3-em-4-carboxylicacid.

Accordingly the present invention provides a cephalosporin compoundhaving a 3-position substituent of the formula (I):

    --CH.sub.2 --Y--Q                                          (I)

wherein Q is:

(i) a benzene ring (optionally fused to a further benzene ring soforming a naphthyl group or optionally fused to a 5 or 6 memberedheterocyclic aromatic group containing 1, 2 or 3 heteroatoms selectedfrom nitrogen, oxygen and sulphur), said benzene ring being substitutedby groups R¹ and R² which are ortho with respect to one another, whereinR¹ is hydroxy or an in vivo hydrolysable ester thereof and R² ishydroxy, an in vivo hydrolysable ester thereof, carboxy, sulpho,hydroxymethyl, methanesulphonamido or ureido;

(ii) a group of the formula (II): ##STR2## or; (iii) a group of theformula (III): ##STR3## wherein M is oxygen or a group NR³ wherein R³ ishydrogen or C₁₋₄ alkyl:

ring Q (or, in the case wherein ring Q is a benzene ring and is fused toanother benzene ring, either benzene ring) is optionally furthersubstituted by C₁₋₄ alkyl, halo, hydroxy, hydroxy C₁₋₄ alkyl, cyano,trifluoromethyl, nitro, amino, C₁₋₄ alkylamino, di-C₁₋₄ alkylamino,amino C₁₋₄ alkyl, C₁₋₄ alkylamino C₁₋₄ alkyl, di-C₁₋₄ alkylamino C₁₋₄alkyl, C₁₋₄ alkanoyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkanoyloxy,carbamoyl, C₁₋₄ alkylcarbamoyl, di-C₁₋₄ alkyl carbamoyl, carboxy,carboxy C₁₋₄ alkyl, sulpho, sulpho C₁₋₄ alkyl, C₁₋₄ alkanesulphonamido,C₁₋₄ alkoxycarbonyl, C₁₋₄ alkanoylamino, nitroso, thioureido, amidino,ammonium, mono- , di-or tri- C₁₋₄ alkylammonium or pyridinium, or a5-membered heterocyclic ring containing 1 to 4 heteroatoms selected fromoxygen, nitrogen and sulphur which is optionally substituted by 1, 2 or3 C₁₋₄ alkyl or C₁₋₄ alkoxy groups,

Y, which links into the benzene ring or the ring of formula (II) or(III), is a covalent bond or is a group --V--Y'-- wherein V is oxygen,sulphur or a group --NR⁴ -- and --Y'-- is a covalent bond or C₁₋₄alkenylene, wherein R⁴ is hydrogen, C₁₋₄ alkyl optionally substituted byany of halo, hydroxy, C₁₋₄ alkoxy, carboxy, amino, cyano, C₁₋₄alkanoylamino, phenyl or heteroaryl, or R⁴ is C₂₋₆ alkenyl, C₁₋₄alkanoyl or C₁₋₄ alkanesulphonyl.

In one aspect V is oxygen, sulphur or a group --NR⁴ -- and Y' is acovalent bond. In a preferred aspect Y is a covalent bond. In anotherpreferred aspect V is oxygen, sulphur or a group --NR⁴ -- and Y' is aC₁₋₄ alkylene group, in particular Y' is methylene.

A particularly preferred linking group Y is --NR⁴ --CH₂ --.

Suitable examples of R⁴ include hydrogen, methyl, ethyl, n-propyl,isopropyl, 2-fluoroethyl, 2-chloroethyl, 2-hydroxymethyl,2-methoxyethyl, carboxymethyl, 2-aminoethyl, 2-cyanoethyl,2-formamidoethyl, allyl, acetyl, propionyl, methanesulphonyl, furfuryl,benzyl and pyrid-4-ylmethyl. Favourably R⁴ is hydrogen, methyl, ethyl,acetyl or methanesulphonyl.

In one aspect ring Q is a benzene ring substituted by groups R¹ and R²as hereinbefore defined. R¹ is hydroxy or an in vivo hydrolysable esterthereof. In vivo hydrolysable esters are those pharmaceuticallyacceptable esters that hydrolyse in the human or animal body to producethe parent hydroxy compound. Such esters can be identified byadministering, e.g. intravenously to a test animal, the compound undertest and subsequently examining the test animal's body fluids. Suitablein vivo hydrolysable esters include C₁₋₆ alkanoyloxy for exampleacetoxy, propionyloxy, pivaloyloxy, C₁₋₄ alkoxycarbonyloxy for exampleethoxycarbonyloxy, phenylacetoxy and phthalidyl.

Conveniently both R¹ and R² have the same value and are both hydroxy orare both in vivo hydrolysable esters, for example they are both acetoxyor both pivaloyloxy.

In one aspect Q is a ring of the formula (III). Suitably M is oxygenthus forming a pyranone ring. Suitably also M is --NH-- in which casethe linking group may be attached to the pyranone ring via the ringnitrogen atom or via a ring carbon atom, in the latter case allowing agreater degree of tautomerism into the hydroxypyridine tautomer. In afurther aspect M is --NR³ wherein R³ is C₁₋₄ alkyl in which case thelinking group Y is attached to the pyranone ring via a ring carbon atom.

In a preferred aspect Q is a benzene ring optionally fused to anotherbenzene ring so forming a naphthyl group. As stated hereinbefore eitherbenzene group may be substituted by R¹ and R² and by other optionalsubstituents. Particular optional substituents are C₁₋₄ alkyl forexample methyl, ethyl or isopropyl, halo for example chloro, bromo orfluoro, hydroxy, hydroxy C₁₋₄ alkyl for example hydroxymethyl, amino,nitro, C₁₋₄ alkoxy for example methoxy or ethoxy, carboxy C₁₋₄ alkyl forexample carboxymethyl, C₁₋₄ alkanoylamino for example acetamido,trifluoromethyl, carboxy, carbamoyl, cyano, sulpho, C₁₋₄alkanesulphonamido for example methanesulphonamido, C₁₋₄ alkanoyl forexample acetyl, C₁₋₄ alkanoyloxy for example acetoxy or propionoxy andC₁₋₄ alkoxycarbonyl for example methoxycarbonyl. Of these, favouredsubstituents are sulpho, carboxymethyl, methyl, ethyl, methoxy, bromo,chloro, fluoro and nitro.

The skilled man will realise that when Q is a benzene ring up to 3optional substituents are possible; when a naphthyl ring is formed moresubstituents are possible and up to 2 or 3 substituents are possiblewith the rings of formulae (II) and (III). In general, we prefer up to 2optional substituents, which may be the same or different.

As stated herein above the present invention relates to cephalosporinshaving a novel 3-position substituent. A particular class ofcephalosporins within the present invention is that of the formula (IV),##STR4## and salts and esters thereof wherein Y and Q are ashereinbefore defined; X is sulphur, oxygen, methylene or sulphlnyl;

R⁶ is hydrogen, methoxy or formamido; and R⁵ and R⁷ are groups known forsuch positions in the cephalosporin art.

Preferably X is sulphur.

Preferably R⁶ is hydrogen.

R⁵ is for example 2-aminothiazol-4-yl or 2-aminooxazol-4-yl eachoptionally substituted in the 5-position by fluorine, chlorine orbromine, or R⁵ is 5-aminoisothiazol-3-yl, 5-amino-1,2,4-thiadiazol-3-yl,3-aminopyrazol-5-yl, 3-aminopyrazol-4-yl, 2-aminopyrimidin-5-yl,2-aminopyrid-6-yl, 4-aminopyrimidin-2-yl, 2-amino-1,3,4-thiadiazol-5-ylor 5-amino-1-methyl-1,2,4-triazol-3-yl;

R⁷ is for example of the formula ═N.O.R⁸ (having the syn configurationabout the double bond) wherein R⁸ is hydrogen, (1-6C)alkyl,(3-8C)cycloalkyl, (1-3C)alkyl(3-6C)cycloalkyl,(3-6C)cycloalkyl(1-3C)alkyl, (3-6C)alkenyl, optionally substituted bycarboxy, (5-8C)cycloalkenyl, (3-6C)alkynyl, (2-5C)alkylcarbamoyl,phenylcarbamoyl, benzylcarbamoyl, (1-4C)alkylcarbamoyl(1-4C)alkyl,di(1-4C)alkylcarbamoyl(1-4C)alkyl, (1-4C)haloalkylcarbamoyl(1-4C)alkyl,(1-3C)haloalkyl, (2-6C)hydroxyalkyl, (1-4C)alkoxy(2-4C)alkyl,(1-4C)alkylthio(2-4C)alkyl, (1-4C)alkanesulphinyl(1-4C)alkyl,(1-4C)alkanesulphonyl(1-4C)alkyl, (2-6C)aminoalkyl,(1-4C)alkylamino(1-6C)alkyl, (2-8C)dialkylamino(2-6C)alkyl,(1-5C)cyanoalkyl, 3-amino-3-carboxypropyl, 2-(amidinothio)ethyl,2-(N-aminoamidinothio)ethyl, tetrahydropyran-2-yl, thietan-3-yl,2-oxopyrrolidinyl, or 2-oxotetrahydrofuranyl, or R⁸ is of the formula V:##STR5## wherein q is one or two and R⁹ and R¹⁰ are independentlyhydrogen or C₁₋₄ alkyl; or R⁸ is of the formula VI:

    --CR.sup.11 R.sup.12 --(CH.sub.2).sub.r --COR.sup.13       VI

wherein r is 0-3, R¹¹ is hydrogen, (1-3C)alkyl or methylthio, R¹² ishydrogen (1-3C)alkyl, (3-7C)cycloalkyl, cyano, carboxy,(2-5C)carboxyalkyl or methanesulphonylamino, or R¹¹ and R¹² are joinedto form, together with the carbon to which they are attached, a(3-7C)carbocyclic ring, and R¹³ is hydroxy, amino, (1-4C)alkoxy, (1-4C)alkylamino or of the formula NHOR¹⁴ in which R¹⁴ is hydrogen or(1-4C)alkyl

or R⁷ may be of the formula ═CH.R¹⁵ wherein R¹⁵ is hydrogen, halogen,(1-6C)alkyl, (3-7C)cycloalkyl, (2-6C)alkenyl, (3-7C)cycloalkenyl, phenylor benzyl.

Particular meanings for R⁸ are hydrogen, methyl, ethyl, isopropyl,t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,methylcyclopropyl, methylcyclobutyl, methylcyclopentyl,methylcyclohexyl, cyclopropylmethyl, cyclobutylmethyl,cyclopentylmethyl, allyl, cyclopentenyl, cyclohexenyl, propargyl,methylcarbamoyl, ethylcarbamoyl, phenylcarbamoyl, benzylcarbamoyl,2-chloroethyl, 2-fluoroethyl, 2-bromoethyl, 2-hydroxyethyl,3-hydroxypropyl, 2-methoxyethyl, 2-ethoxyethyl, 2-methylthio-ethyl,2-methanesulphinylethyl, 2-methanesulphonyl-ethyl, 2-aminoethyl,3-aminopropyl, 2-methylamino ethyl, 2-dimethylaminoethyl, cyanomethyl,2-cyanoethyl, azidomethyl, 2-azidoethyl, ureidomethyl,3-amino-3-carboxypropyl, 2-(amidino)ethyl, 2-(N-aminoamidino)-ethyl,tetrahydropyran-2-yl, thietan-3-yl, 2-oxopyrrolidinyl and2-oxotetrahydrofuran-3-yl,

or, when R⁸ is of the formula V in which q is 1 or 2, a particularmeaning for R⁸ is when R⁹ and R¹⁰ are hydrogen or methyl,

or, when R⁸ is of the formula VI, a particular meaning for R⁸ is whenr=0 and R¹¹ is hydrogen, methyl or methylthio, R¹² is hydrogen, methyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyano, carboxy,carboxymethyl, 2-carboxyethyl or methanesulphonylamino, or when R¹¹ andR¹² are joined to form, together with the carbon to which they areattached, a cyclopropane, cyclobutane, cyclopentane, cyclohexane orcycloheptane ring and R¹³ is hydroxy, amino, methoxy, ethoxy,methylamino, ethylamino, or of the formula NHOR¹⁴ in which R¹⁴ ishydrogen, methyl or ethyl.

Preferably R⁸ is C₁₋₆ alkyl for example methyl or ethyl,1-carboxycyclobutyl, 1-carboxycyclopentyl, or 2-carboxyprop-2-yl. Inparticular R⁸ is 2-carboxyprop-2-yl.

Particular meanings for R¹⁵ are hydrogen, methyl, ethyl or chlorine.

Preferred compounds of the present invention include:

3-(3,4-dihydroxybenzoylaminomethyl)-7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]ceph-3-em-4-carboxylicacid; and

3-(3,4-dihydroxybenzyl)-7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]ceph-3-em-4-carboxylicacid.

The cephalosporin derivatives referred to herein are generally named inaccordance with the `cephem` nomenclature and numbering system proposedin J.A.C.S. 1962, 84, 3400.

It will be realised, of course, that the present invention covers allisomeric and tautomerlc forms of the aforementioned compounds. Forexample the rings of the formula (III) may be in pyranone orhydroxypyridine form.

As stated hereinbefore the compounds of this invention ar primarilyintended for use in therapy. Therefore in a preferred aspect the presentinvention provides a cephalosporin compound having a 3-positionsubstituent of the formula I or a pharmaceutically acceptable salt orester thereof. Suitable salts include acid addition salts such ashydrochloride, hydrobromide, citrate, maleate and salts formed withphosphoric and sulphuric acid. In another aspect suitable salts are basesalts such as an alkali metal salt for example sodium or potassium, analkaline earth metal salt for example calcium or magnesium, an organicamine salt for example triethylamine, morpholine, N-methylpiperidine,N-ethylpiperidine, procaine, dibenzylamine, or N,N-dibenzylethylamine.

In order to use a compound of the present invention or apharmaceutically acceptable salt or ester thereof for the therapeutictreatment of mammals including humans, in particular in treatinginfection, it is normally formulated in accordance with standardpharmaceutical practice as a pharmaceutical composition.

Therefore in another aspect the present invention provides apharmaceutical composition which comprises a cephalosporin compoundhaving a 3-position substituent of the formula I or a pharmaceuticallyacceptable salt or ester thereof and a pharmaceutically acceptablecarrier.

The pharmaceutical compositions of this invention may be administered instandard manner for the disease condition that it is desired to treat,for example by oral, rectal or parenteral administration. For thesepurposes it may be formulated by means known to the art into the formof, for example, tablets, capsules, aqueous or oily solutions orsuspensions, emulsions, dispersible powders, suppositories and sterileinjectable aqueous or oily solutions or suspensions.

In addition to the pharmaceutically acceptable cephalosporin derivativeof the present invention the pharmaceutical composition of the inventionmay also contain, or be co-administered with, one or more known drugsselected from other clinically useful antibacterial agents (for exampleother beta-lactams or aminoglycosides), inhibitors of beta-lactamase(for example clavulanic acid), renal tubular blocking agents (e.g.probenicid) and inhibitors of metabolising enzymes (for exampleinhibitors of peptidases, for example Z-2-acylamino-3-substitutedpropenoates).

A preferred pharmaceutical composition of the invention is one suitablefor intravenous, subcutaneous or intramuscular injection, for example asterile injectable containing between 1 and 50% w/w of the cephalosporinderivative, or one suitable for oral administration in unit dosage form,for example a tablet or capsule which contains between 100 mg. and 1 g.of the cephalosporin derivative.

The pharmaceutical compositions of the invention will normally beadministered to man in order to combat infections caused by bacteria, inthe same general manner as that employed for cephalothin, cefoxitin,cephradine, ceftazidime and other known clinically used cephalosporinderivatives, due allowance being made in terms of dose levels for thepotency of the cephalosporin derivative of the present inventionrelative to the known clinically used cephalosporins. Thus each patientwill receive a daily intravenous, subcutaneous or intramuscular dose of0.05 to 30 g., and preferably 0.1 to 10 g., of the cephalosporinderivative, the composition being administered 1 to 4 times per day,preferably 1 or 2 times a day. The intravenous, subcutaneous andintramuscular dose may be given by means of a bolus injection.Alternatively the intravenous dose may be given by continuous infusionover a period of time. Alternatively each patient will receive a dailyoral dose which is approximately equivalent to the daily parenteraldose. Thus a preferred daily oral dose is 0.5 to 10 g. of thecephalosporin derivative, the composition being administered 1 to 4times per day.

In a further aspect the present invention provides a process forpreparing a cephalosporin compound having a 3-position substituent ofthe formula I, which process comprises;

(a) reacting a cephalosporin compound having a 3-position substituent ofthe formula: --CH₂ L wherein L is a leaving group, with a source of--Y--Q wherein Y and Q are as hereinbefore defined;

(b) for preparing a compound wherein Y is a group --V--Y'--, reacting acephalosporin compound having a 3-position substituent of the formula:--CH₂ VH with a source of --Y'--Q wherein V, Y' and Q are ashereinbefore defined;

(c) for preparing compounds of the formula (IV), reacting a compound ofthe formula (VII) with a compound of the formula (VIII) or a reactivederivative thereof: ##STR6## wherein R⁵, R⁶, R⁷, X, Y and Q are ashereinbefore defined or

d) for compounds of the formula (IV) wherein R⁷ is a group ═NOR⁸,reacting a compound of the formula (IX): ##STR7## wherein R⁵, R⁶, X, Yand Q are as hereinbefore defined, with a compound of the formula, R⁸ONH₂ wherein R⁸ is as hereinbefore defined; or

e) for compounds of the formula (IV) wherein R⁷ is a group ═NOR⁸ and R⁸is other than hydrogen, reacting a compound of the formula (IV) ashereinbefore defined wherein R⁷ is a group ═NOH with a compound of theformula (X):

    L.sup.1 --R.sup.16                                         (X)

wherein L¹ is a leaving group and R¹⁶ is a group R⁸ other than hydrogen:or

f) for compounds of the formula (IV) forming a group R⁵ by cyclising anappropriate precursor thereof:

wherein any functional groups are optionally protected:

and thereafter, if necessary:

i) removing any protecting group,

ii) for preparing in vivo hydrolysable esters, esterifying correspondinghydroxy groups,

iii) converting compounds wherein X is S to compounds wherein X issulphinyl and vice versa,

iv) converting compounds wherein R⁴ is one value to compounds wherein R⁴has another value,

v) forming a pharmaceutically acceptable salt.

In the reaction between a cephalosporin compound having a 3-positionsubstituent of the formula: --CH₂ L and a source of --Y--Q, convenientlyL is a leaving group such as halo for example iodo, bromo or chloro, oris C₁₋₄ alkanoyloxy for example acetoxy. This reaction is most suitablefor forming cephalosporin compounds wherein the 3-position substituentis substituted benzyl or substituted naphthylmethyl. Typically thereaction is performed in the presence of boron trifluoride catalyst in asubstantially inert solvent such as acetonitrile at a non-extremetemperature for example ambient.

The reaction between a cephalosporin compound having a 3-positionsubstituent of the formula: --CH₂ VH and a source of --Y'--Q, may beperformed in conventional manner. For example reference may be made toGB 1496757. In a preferred aspect cephalosporin compounds having a3-position substituent of the formula: --CH₂ N(R⁴)--CH₂ --Q can beprepared by reacting a cephalosporin having a 3-CH₂ NHR₄ substituentwith an aldehyde (or equivalent) of the formula: QCHO in the presence ofa reducing agent for example a borohydride. Such reductive aminationscan be performed in conventional manner in a substantially inert solventfor example methanol at a non-extreme temperature for example ambient.

The cephalosporin starting materials for these reactions are known fromthe art, or are made by methods analogous thereto. See for example GB1496757, EP-A-127992 and EP-A-164944.

The reaction between compounds of the formulae (VII) and (VIII) isperformed under conditions conventional in the cephalosporin art, forexample under standard acylation conditions wherein for example the acidis activated as an acid bromide, acid chloride, anhydride or activatedester, or the reaction is performed in the presence of a couplingreagent such as dicyclohexylcarbodi-imide.

The compounds of the formula (VII) can be prepared in a manner analogousto that described for the compounds of the formula (I), with the 7-aminogroup being optionally protected.

The reaction between compounds of the formula (IX) and R⁸ ONH₂ isperformed under conditions standard in the general chemical and/orcephalosporin art. The compounds of the formula (IX) can be prepared ina manner analogous to that described for the compounds of the formula(I).

The reaction between the compound of the formula (IV) wherein R⁷ is agroup ═NOH and a compound of the formula (X) is performed underconditions standard in the general chemical and/or cephalosporin art.

A group R⁵ may be formed by cyclizing an appropriate precursor. Forexample compounds of the formulae (XI) and (XII): ##STR8## wherein R⁷,R⁶, X, Y and Q are as hereinbefore defined and L² is a leaving group,may be reacted to form a 2-aminothiazol-4-yl group. A nitrogen atom ofthe thiourea may be optionally protected during this cyclization.

The compounds of the formula (XI) can be prepared in a manner analogousto that described for the compounds of the formula I.

The compounds of the formulae (VIII), (X) and R⁸ ONH₂ are known from, orcan be made by the methods of, the general chemical and/or cephalosporinart.

The compounds of the formulae (VII), (IX) and (XI) are novel and as suchform a further aspect of the present invention.

In the process of this invention any functional group can be optionallyprotected, if appropriate. Such protecting groups may in general bechosen from any of the groups described in the literature or known tothe skilled chemist as appropriate for the protection of the group inquestion, and may be introduced by conventional methods.

Protecting groups may be removed by any convenient method as describedin the literature or known to the skilled chemist as appropriate for theremoval of the protecting group in question, such methods being chosenso as to effect removal of the protecting group with minimum disturbanceof groups elsewhere in the molecule.

Specific examples of protecting groups are given below for the sake ofconvenience, in which "lower" signifies that the group to which it isapplied preferably has 1-4 carbon atoms. It will be understood thatthese examples are not exhaustive. Where specific examples of methodsfor the removal of protecting groups are given below these are similarlynot exhaustive. The use of protecting groups and methods of deprotectionnot specifically mentioned Is of course within the scope of theinvention.

A carboxyl protecting group may be the residue of an ester-formingaliphatic or araliphatic alcohol or of an ester-forming phenol, silanolor stannanol (the said alcohol, phenol, silanol or stannanol preferablycontaining 1-20 carbon atoms).

Examples of carboxyl protecting groups include straight or branchedchain (1-12C)alkyl groups (e.g. isopropyl, t-butyl); halo lower alkylgroups (e.g. 2-iodoethyl, 2,2,2-trichloroethyl); lower alkoxy loweralkyl groups (e.g. methoxymethyl, ethoxymethyl, isobutoxymethyl); loweraliphatic acyloxy lower alkyl groups, (e.g. acetoxymethyl,propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl); loweralkoxycarbonyloxy lower alkyl groups (e.g. 1-methoxycarbonyloxyethyl,1-ethoxycarbonyloxyethyl); aryl lower alkyl groups (e.g.p-methoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, benzhydryl andphthalidyl) tri(lower alkyl)silyl groups (e.g. trimethylsilyl andt-butyldimethylsilyl); tri(lower alkyl)silyl lower alkyl groups (e.g.trimethylsilylethyl) and (2-6C)alkenyl groups (e.g. allyl andvinylethyl).

Methods particularly appropriate for the removal of carboxyl protectinggroups include for example acid-, base-, metal- or enzymically-catalysedhydrolysis.

Examples of hydroxyl protecting groups include lower alkanoyl groups(e.g. acetyl); lower alkoxycarbonyl groups (e.g. t-butoxycarbonyl) halolower alkoxycarbonyl groups (e.g. 2-iodoethoxycarbonyl,2,2,2-trichloroethoxycarbonyl); aryl lower alkoxycarbonyl groups (e.g.benzoyloxycarbonyl, p-methoxybenzyloxycarbonyl,o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl); tri loweralkylsilyl (e.g. trimethylsilyl, t-butyldimethylsilyl) and aryl loweralkyl (e.g. benzyl) groups. In addition two hydroxy groups substitutedon adjacent carbon atoms, for example in the catechol moiety, may beprotected in the form of a cyclic acetal such as the methylenedioxymoiety.

Examples of amino protecting groups include formyl, aralkyl groups (e.g.benzyl and substituted benzyl, e.g. p-methoxybenzyl, nitrobenzyl and2,4-dimethoxybenzyl, and triphenylmethyl) di-p-anisylmethyl andfurylmethyl groups; acyl (e.g. alkoxycarbonyl and aralkoxycarbonyl e.g.t-butoxycarbonyl and benzyloxycarbonyl), trialkylsilyl (e.g.trimethylsilyl and t-butyldimethylsilyl), alkylidene (e.g. methylidene),benzylidene and substituted benzylidene groups, and the phthalimidogroup.

Esterification of hydroxy groups (i.e. R¹ and R²) to form in vivohydrolysable esters is performed in conventional manner. Reduction of acephalosporin sulphoxide to a cephalosporin and oxidation of asulphoxide to a sulphide are performed according to methods known in theart. An example of converting one group R⁴ to another group R⁴ is theacylation of --NH-- to --N(COC₁₋₄ alkyl)-- or to --N(SO₂ C₁₋₄ alkyl)--.

The following biological test methods, data and Examples serve toillustrate this invention.

Antibacterial Activity

The pharmaceutically acceptable cephalosporin compounds of the presentinvention are useful antibacterial agents having a broad spectrum ofactivity in vitro against standard laboratory microorganisms, bothGram-negative and Gram-positive, which are used to screen for activityagainst pathogenic bacteria. The antibacterial spectrum and potency of aparticular compound may be determined in a standard test system. Thecompounds have particularly high activity in vitro against strains ofPseudomonas aeruginosa.

The antibacterial properties of the compounds of the invention may alsobe demonstrated in vivo in conventional mouse protection tests.

In addition representative compounds of this invention show prolongedduration, as evidenced by half-life values, in test animals.

Cephalosporin derivatives have generally been found to be relativelynon-toxic to warm-blooded animals, and this generalisation holds truefor the compounds of the present invention. Compounds representative ofthe present invention were administered to mice at doses in excess ofthose required to afford protection against bacterial infections, and noovert toxic symptoms or side effects attributable to the administeredcompounds were noted.

The following results were obtained for representative compounds on astandard in vitro test system using Isosensitest agar medium. Theantibacterial activity is described in terms of the minimum inhibitoryconcentration (M1C) determined by the agar-dilution technique with aninoculum size of 10⁴ CFU/spot.

    ______________________________________                                                  MIC (μl/ml)                                                                EXAMPLE                                                             ORGANISM    3       6          9     20                                       ______________________________________                                        P. aeruginosa                                                                             4       0.25       0.25  2                                        PU21 (A8101028)                                                               Ent. cloacae                                                                              4       2          4     8                                        P99 (A8401054)                                                                Serr. marcesens                                                                           0.5     0.25       NA    4                                        (A8421003)                                                                    Pr. morganii                                                                              2       0.25       1     16                                       (A8433001)                                                                    Kleb. aerogenes                                                                           0.125   0.06       0.06  4                                        (A8391027)                                                                    E. coli     0.125   0.06       0.125 1                                        DCO (A8341098)                                                                St. aureus  4       16         16    8                                        147N (A8601052)                                                               S. dublin   2       0.25       0.25  8                                        (A8369001)                                                                    Strep. pyogenes                                                                           0.008   0.125      0.25  NA                                       (A681018)                                                                     ______________________________________                                    

In the following Examples the following abbreviations are used:

AcOH=acetic acid

DMF=dimethylformamide

DMSO=dimethylsulphoxide

EtOAc=ethyl acetate

EtOH=ethanol

HPLC=high performance liquid chromatography

MeOH=methanol

NMR=nuclear magnetic resonance spectroscopy

TEA=triethylamine

TFA=trifluoroacetic acid

The NMR spectra are taken at 90 MHz and are quoted in terms of deltavalues in parts per million (ppm) with reference to tetramethylsilane(delta=0). The solvent used was DMSOd₆ /CD₃ COOD/TFA except whereotherwise indicated. In the quotation of NMR data s=singlet, d=doublet,t=triplet, q=quartet, m=multiplet, br=broad.

EXAMPLES 1-7

The following general procedure was used for the preparation of thecompounds of Examples 1-7, of which particulars are given in Tables Iand II.

To a suspension of the appropriate7-substituted-3-aminomethyl-ceph-3-em-4-carboxylic acid (0.5 mmole) inMeOH (15 ml) containing a few drops of water, and maintained at pH5.5-6.0 was added 3,4-dihydroxybenzaldehyde (0.55 mmole) and then sodiumcyanoborohydride (0.5 mmole).

The pH was maintained at pH 5.5-6.0 by addition of sodium bicarbonate oracetic acid as appropriate, and further portions of sodiumcyanoborohydride were added over 4 hours until none of the cephalosporinstarting material remained (monitored by HPLC). The solvents wereevaporated and the mixture purified on a Diaion HP20SS resin columnusing MeOH/H₂ O mixtures of increasing proportions of MeOH andcontaining AcOH (1%). Evaporation and freeze drying of the appropriatefractions gave the product in the yield indicated.

Particulars of the compounds prepared, and the yields obtained, aregiven in Table I. NMR characterising data is given in Table II.

                                      TABLE I                                     __________________________________________________________________________     ##STR9##                                                                     Example No.                                                                             R2          Yield (%)                                                                              Footnotes                                      __________________________________________________________________________    1         C.sub.2 H.sub.5                                                                           27                                                      2         CH.sub.2 CH.sub.2 F                                                                       40                                                      3         CH.sub.2 CH.sub.2 Cl                                                                      57                                                      4         CH.sub.3    25                                                      5         CH.sub.2 CF.sub.3                                                                         33                                                                 ##STR10##  13                                                      7         CH.sub.2COOH                                                                              48       1                                              __________________________________________________________________________     Footnotes                                                                     1. The general method indicated was used to prepare the diacetoxy             derivative using 3,4diacetoxybenzaldehyde instead of the 3,4dihydroxy         compound and the resulting compound                                           7[2-(2-aminothiazol-4-yl)-2-((Z)-carboxymethoxyimino)acetamido]-3-(3,4-di    cetoxybenzyl)aminomethylceph-3-em-4-carboxylic acid (130 mg) deprotected b     dissolving in H.sub.2 O (50 ml) containing ammonium carbonate (100 mg) at     pH 7-7.5. The solution was left to stand for 2 days until no cephalospori     starting material remained. The mixture was purified on a Diaion HP20SS       resin column and isolated as described above.                            

                  TABLE II                                                        ______________________________________                                        NMR data for the compounds of Table I taken at 90 MHz in                      DMSOd.sub.6 /CD.sub.3 CO.sub.2 D/TFAd                                         Example                                                                       No.    Delta Values (ppm).                                                    ______________________________________                                        1      2.5(t,3H); 3.65(m, 2H); 3.8(m, 2H); 4.0(m, 2H);                               4.25(q, 2H); 5.15(d, 1H); 5.85(d, 1H); 6.75(s, 2H);                           6.90(s, 1H); 7.0(s, 1H).                                               2      3.65(m, 2H); 385(m, 2H); 4.0(m, 2H); 4.4(m, 2H);                              4.6(t, 1H); 5.0(t, 1H); 5.2(d, 1H); 5.85(d, 1H);                              6.75(s, 2H); 6.9(s, 1H); 7.0(s, 1H).                                   3      3.65(m, 2H); 3.7-4.1(m, 6H); 4.4(t, 2H); 5.15(d, 1H);                         5.85(d, 1H); 6.75(s, 2H); 6.9(s, 1H); 7.05(s, 1H).                     4      3.65(m, 2H); 3.85(m, 2H); 4.0(m, 2H); 4.0(s, 3H);                             5.15(d, 1H); 5.85(d, 1H); 6.75(s, 2H); 6.9(s, 1H);                            7.0(s, 1H).                                                            5      3.65(m, 2H); 3.85(m, 2H); 4.0(m, 2H); 4.75(q, 2H);                            5.2(d, 1H); 5.85(d, 1H); 6.8(s, 2H); 6.9(s, 1H);                              7.05(s, 1H).                                                           6      1.55(s, 6H); 3.65(m, 2H); 3.7-3.9(m, 2H); 4.0(m, 2H);                         5.15(d, 1H); 5.9(d, 1H); 6.75(s, 2H); 6.9(s, 1H);                             7.05(s, 1H).                                                           7      3.6-4.1(m, 6H); 4.75(s, 2H); 5.2(d, 1H); 5.9(d, 1H);                          6.8(s, 2H); 6.85(s, 1H); 7.05(s, 1H).                                  ______________________________________                                    

EXAMPLE 83-(3,4-Dihydroxybenzylaminomethyl)-7-[2-(aminothiazol-4-yl)-2-((Z)-1-carboxycyclopentyloxyimino)acetamido]-ceph-3-em-4-carboxylicacid

To a suspension of3-aminomethyl-7-[2-(aminothiazol-4-yl)-2-((Z)-1-carboxycyclopentyloxyimino)acetamido]ceph-3-em-4-carboxylicacid (153 mg) in water (10 ml) with sufficient triethylamine to obtain asolution (pH 7.5) was added 3,4-dihydroxybenzaldehyde (41 mg) and thensodium cyanoborohydride (19 mg). The pH was adjusted and furthermaintained at pH 5.4 and further portions (×4) of sodiumcyanoborohydride and 3,4-dihydroxybenzaldehyde added over 24 hours untilno cephalosporin starting material remained. The aqueous solution waswashed three times with ether and concentrated, and the crude mixturepurified by HPLC on an octadecylsilane column using MeOH/water/AcOH,20-30:79-69:1 as eluant. Evaporation and freeze drying yielded 80 mg(48%) of the title compound, NMR in DMSOd₆ +CD₃ CO₂ D+TFA_(d) ;1.81(s,4H); 2.15(m,4H); 3.4 to 4.2(m,6H); 5.17(d,1H); 5.9(d,1H);6.76(br.s,2H); 6.89(br.s,1H); 7.04(s,1H).

EXAMPLES 9-20

The following general procedure was used for the preparation of thecompounds of Examples 9-20, of which particulars are given in Tables IIIand IV.

To a solution of 7-amino-3-acetoxymethylceph-3-em-4-carboxylic acid(7-ACA) (1 mmole) in acetonitrile/BF₃.Et₂ O (4/1) at room temperature,was added the appropriate dihydroxy benzene or naphthalene derivative (1mmole). Stirring was continued at room temperature for 2 to 3 hours, theprogress of the reaction being followed by analytical HPLC. At the endof the reaction the solvents were evaporated and the crude productpurified by medium pressure chromatography on a Diaion HP20SS column,using MeOH/water with 1% AcOH, the percentage of MeOH being slowlyincreased from 0 to 100%.

The 7-amino cephalosporin intermediate thus produced was dissolved inCH₂ Cl₂ with 4-5 equivalents of bis-trimethylsilylacetamide (BSA) atroom temperature under argon, several hours being necessary to achievecomplete dissolution. To this solution was added a solution of theappropriate 7-side chain carboxylic acid (carboxy groups on the oximeprotected as the t-butoxy derivative and the aminothiazolyl protected asthe trityl derivative) in the form of the acid chloride or an activeester (e.g. with N-hydroxybenzotriazole (HOBT)). The mixture was shakenat room temperature for several hours, the solvent evaporated and theproduct treated with TFA/water at room temperature for two hours toremove all protecting groups. The compound was then purified by HPLC ormedium pressure chromatography.

Particulars of the compounds prepared, and the yields obtained, aregiven in Table III. NMR characterising data is given in Table IV.

                  TABLE III                                                       ______________________________________                                         ##STR11##                                                                    Example No.                                                                            R2          Q             Yield (%)                                  ______________________________________                                         9                                                                                      ##STR12##                                                                                 ##STR13##    22                                         10       CH.sub.3                                                                                   ##STR14##    30                                         11                                                                                      ##STR15##                                                                                 ##STR16##    17                                         12       CH.sub.3                                                                                   ##STR17##    20                                         13                                                                                      ##STR18##                                                                                 ##STR19##    62                                         14                                                                                      ##STR20##                                                                                 ##STR21##    10                                         15       C.sub.2 H.sub.5                                                                            ##STR22##    37                                         16       C.sub.2 H.sub.5                                                                            ##STR23##    24                                         17       C.sub.2 H.sub.5                                                                            ##STR24##    20                                         18       C.sub.2 H.sub.5                                                                            ##STR25##    21                                         19       C.sub.2 H.sub.5                                                                            ##STR26##    12                                         20       C.sub.2 H.sub.5                                                                            ##STR27##    42                                         ______________________________________                                    

                  TABLE IV                                                        ______________________________________                                        NMR data for the compounds of Table III taken at 90 MHz in                    DMSOd.sub.6 /AcOD/TFA.                                                        Example                                                                       No.    Delta values (ppm)                                                     ______________________________________                                         9     1.52(s, 6H), 3.35 and 3.5(2d, 2H), 3.2-4.1(m, 2H);                            5.17(d, 1H), 5.77(d, 1H), 6.5-6.9(m, 3H);                                     7.05(s, 1H).                                                           10     3.2 and 3.5(2d, 2H); 3.3-4.1(m, 2H); 4.0(s, 3H);                              5.17(d, 1H); 5.7(d, 1H); 6.5-6.85(m, 3H); 7.0(s, 1H).                  11     1.5(s, 6H); 3.14(m, 2H); 4.4(m, 2H); 5.14(d, 1H);                             5.7(d, 1H); 7.05(s, 1H); 7.05-8(m, 5H).                                12     3.1(m, 2H); 4(s, 3H); 4.4(m, 2H); 5.1(d, 1H);                                 5.6(d, 1H); 7(s, 1H); 7.1(s, 1H); 7.1-8(m, 4H).                        13     1.5(s, 6H); 3.1(m, 2H); 4.4(m, 2H); 5.1(d, 1H);                               5.7(d, 1H); 7.05(s, 1H): 7.15(s, 1H); 7.6(m, 2H);                             8.2(s, 1H).                                                            14     1.5(s, 6H); 3.1 and 3.4(2d, 2H); 4.1-4.3(m, 2H);                              5.15(d, 1H); 5.75d, 1H); 7.08(m, 2H); 7.2-                                    8.3(m, 4H).                                                            15     1.27(t, 3H); 3.1 and 3.4(2d, 2H); 3.44(m, 2H); 3.5-                           3.8(m, 2H); 4.24(q, 2H); 5.15(d, 1H); 5.75(d, 1H);                            6.6(s, 2H); 7.0(s, 1H).                                                16     1.25(t, 3H); 3.15 and 3.45(2d, 2H); 3.2-4(m, 2H);                             4.2(q, 2R); 5.15(d, 1H); 5.7(d, 1H); 6.4-6.8(m, 2H)                           6.7(s, 1H); 7.0(s, 1H).                                                17     1.15(t, 3H); 3.1-3.3(m, 2H); 3.75(m, 2H); 4.2(q, 2H);                         5.15(d, 1H); 5.65(d, 1H); 6.5(s, 1H); 6.6(s, 1H);                             6.95(s, 1H).                                                           18     1.15(t, 3H); 2.05(s, 3H); 3.1 and 3.35(2d, 2H); 3.5                           and 3.75(2d, 2H); 4.24(q, 2H); 5.15(d, 1H);                                   5.7(d, 1H); 6.55(2s, 2H); 7.0(s, 1H).                                  19     1.25(t, 3H); 3.7(s, 3H); 3-4(m, 4H); 4.24(q, 2H);                             5.1(d, 1H); 5.65(d, 1H); 6.45(s, 2H); 6.95(s, 1H).                      20*   1.05(t, 3H); 1.26(t, 3H); 2.45(q, 2H); 3.1 and                                3.4(2d, 2H); 3.5 and 3.8(2d, 2H); 4.24(q, 2H);                                5.15(d, 1H); 5.7(d, 1H); 6.55(s, 2H); 7.0(s, 1H).                      ______________________________________                                         *Solvent = CF.sub.3 CO.sub.2 D/CD.sub.3 CO.sub.2 D/DMSOd.sub.6 -         

EXAMPLE 21

7-[2-(2-Aminothiazol-4-yl)-2-((Z)-ethoxyimino)acetamido-3-(N-3,4-diacetoxybenzyl)aminomethyl]-ceph-3-em-4-carboxylic acid (19O mg, 0.3 mmol) wassuspended in acetonitrile (4 ml), the suspension was cooled to 0° C.,and treated, in quick succession, with triethylamine (61 mg; 83 μl, 0.6mmol) and acetyl chloride (24 mg, 22 μl, 0.3 mmol). The mixture wasstirred at 0° for 1 hour, the acetonitrile removed under reducedpressure and the residue so obtained applied to a Diaion HP 20 SS resincolumn in H₂ O/DMF. The column was developed by gradient elution (H₂O--20% CH₃ CN/H₂ O), the appropriate fractions combined, acetonitrileremoved and7-[2-(2-aminothiazol-4-yl)-2((Z)-ethoxyimino)acetamido-3-(N-acetyl-N-3,4-diacetoxybenzyl)aminomethyl]-ceph-3-em-4-carboxylicacid obtained (in 36% yield) by freeze-drying; NMR (d₆ DMSO,d₄ HOAC)1.18(t,3H); 2.02, 2.12(s,s,3H, 2 rotamers); 2.21(s, 6H); 3.30(d, 1H);3.45(d,d, 1H); 4.09(q, 2H); 4.2-4.65(m, 2H); 5.03, 5.06(d,d, 1H, 2rotamers); 5.76(d,d, 1H, 2 rotamers), 6.61(s, 1H), 7-7.25(m, 3H).

EXAMPLE 22

7-[2-(2-Aminothiazol-4-yl)-2-((Z)-ethoxyimino)acetamido-3-(N-3,4-diacetoxybenzyl)aminomethyl]-ceph-3-em-4-carboxylicacid (250 mg, 0.4 mmol) was suspended in acetonitrile (5 ml), thesuspension cooled to 0° C., treated with triethylamine (80 mg, 109 μl,0.8 mmol) and, subsequently, with methanesulphonylchlorlde (45 mg, 31μl, 0.4 mmol). The mixture was stirred for 10 minutes before addingfurther triethylamine (80 mg, 0.8 mmol). After stirring for a further11/2 hours the mixture was poured on to H₂ O (75 ml) and the solutionpurified by chromatography on Diaion HP 20 SS resin (gradient elution,H₂ O--20% CH₃ CN/H₂ O. Appropriate fractions were combined, acetonitrileremoved under reduced pressure and triethylammonium7-[2-(2-aminothiazol-4-yl)-2-((Z)-ethoxyimino)acetamido-3-(N-3,4-diacetoxybenzyl-N-methanesulphonyl)aminomethyl]-ceph-3-em-4-carboxylateisolated by freeze-drying (48% yield); NMR (d₆ DMSO,d₄ HOAc) 1.16 (t,9H); 1.2(t, 3H); 2.2(s, 3H); 2.22(s, 3H); 2.97(s, 3H); 3.08(q, 6H);3.24(s, 2H); 4.08(q, 2H); 4.19(d, 1H); 4.20(br, 2H); 4.45(d, 1H);4.77(d, 1H); 5.68(d, 1H); 6.7(s, 1H); 7.1-7.3(m, 3H).

I claim:
 1. A cephalosporin compound of the formula (IV): ##STR28## or asalt or ester thereof; wherein, X is sulphur or sulphinyl;R⁶ ishydrogen, methoxy or formamido; R⁵ is 2-aminothiazol-4-yl or2-aminooxazol-4-yl each unsubstituted or substituted in the 5-positionby fluorine, chlorine or bromine, or R⁵ is 5-aminoisothiazol-3-yl,5-amino-1,2,4-thiadiazol-3-yl, 3-aminopyrazol-5-yl, 3-aminopyrazol-4-yl,2-aminopyrimidin-5-yl, 2-aminopyrid-6-yl, 4-aminopyrimidin-2-yl,2-amino-1,3,4-thiadiazol-5-yl or 5-amino-1-methyl-1,2,4-triazol-3-yl; R⁷is of the formula ═N.O.R⁸ (having the syn configuration about the doublebond) wherein R⁸ is hydrogen, (1-6C)alkyl, (3-8C)cycloalkyl,(1-3C)alkyl(3-6C)cycloalkyl, (3-6C)cycloalkyl(1-3C)alkyl, (3-6C)alkenyl,carboxy(3-6C)alkenyl, (5-8C)cycloalkenyl, (3-6C)alkynyl,(2-5C)alkylcarbamoyl, phenylcarbamoyl, benzylcarbamoyl,(1-4C)alkylcarbamoyl (1-4C)alkyl, di(1-4C)alkylcarbamoyl(1-4C)alkyl,(1-4C)haloalkylcarbamoyl(1-4C)alkyl, (1-3C)haloalkyl,(2-6C)hydroxyalkyl, (1-4C)alkoxy(2-4C)alkyl, (1-4C)alkylthio(2-4C)alkyl, (1-4C)alkanesulphinyl(1-4C)alkyl,(1-4C)alkanesulphonyl(1-4C)alkyl, (2-6C)aminoalkyl, (1-4C)alkylamino(1-6C)alkyl, (2-8C)dialkylamino(2-6C)alkyl,(1-5C)cyanoalkyl, 3-amino-3-carboxypropyl, 2-(amidinothio)ethyl,2-(N-aminoamidinothio)ethyl, tetrahydropyran-2-yl, thietan-3-yl,2-oxopyrrolidinyl, or 2-oxotetrahydrofuranyl, or R⁸ is of the formula V:##STR29## wherein q is one or two and R⁹ and R¹⁰ are independentlyhydrogen or C₁₋₄ alkyl; or R⁸ is of the formula VI:

    --CR.sup.11 R.sup.12 --(CH.sub.2).sub.r --COR.sup.13       VI

wherein r is 0-3, R¹¹ is hydrogen, (1-3C)alkyl or methylthio, R¹² ishydrogen (1-3C)alkyl, (3-7C)cycloalkyl, cyano, carboxy,(2-5C)carboxyalkyl or methanesulphonylamino, or R¹¹ and R¹² are joinedto form, together with the carbon to which they are attached, a(3-7C)carbocyclic ring, and R¹³ is hydroxy, amino, (1-4C)alkoxy, (1- 4C)alkylamino or of the formula NHOR¹⁴ in which R¹⁴ is hydrogen or(1-4C)alkyl; or R⁷ may be of the formula ═CH.R¹⁵ wherein R¹⁵ ishydrogen, halogen, (1-6C)alkyl, (3-7C)cycloalkyl, (2-6C)alkenyl,(3-7C)cycloalkenyl, phenyl or benzyl; wherein Q is:a benzene ring(optionally fused to a further benzene ring so forming a naphthyl groupor optionally fused to a 5 or 6 membered heterocyclic aromatic groupcontaining 1, 2 or 3 heteroatoms selected from the nitrogen, oxygen andsulphur), said benzene ring being substituted by groups R¹ and R² whichare ortho with respect to one another, wherein R¹ is hydroxy or a C₁₋₄alkanoyloxy and R² is hydroxy, or a C₁₋₄ alkanoyloxy,wherein ring Q (or,in the case wherein ring Q is a benzene ring fused to another benzenering, either benzene ring) is optionally substituted by C₁₋₄ alkyl,halo, hydroxy, hydroxy C₁₋₄ alkyl, cyano, trifluoromethyl, nitro, amino,C₁₋₄ alkylamino, di-C.sub. 1-4 alkylamino, amino C₁₋₄ alkyl, C₁₋₄alkylamino C₁₋₄ alkyl, di-C₁₋₄ alkylamino C₁₋₄ alkyl, C₁₋₄ alkanoyl,C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkanoyloxy, carbamoyl, C₁₋₄alkylcarbamoyl, di-C₁₋₄ alkyl carbamoyl, carboxy, carboxy C₁₋₄ alkyl,sulpho, sulpho C₁₋₄ alkyl, C₁₋₄ alkanesulphonamido, C₁₋₄ alkoxycarbonyl,C₁₋₄ alkanoylamino, nitroso, thioureido, amidino, ammonium, mono-, di-or tri- C₁₋₄ alkylammonium or pyridinium, or a 5-membered heterocyclicring containing 1 to 4 heteroatoms selected from oxygen, nitrogen andsulphur which is optionally substituted by 1, 2 or 3 C₁₋₄ alkyl or C₁₋₄alkoxy groups; Y, which links into the benzene ring, is a covalent bond.2. The compound according to claim 1 that is3-(3,4-dihydroxybenzyl)-7-[2-(2-aminothiazol-4-yl)-2-(Z)-1-carboxy-1-methylethoxyimino)acetamido]ceph-3-em-4-carboxylic acid.
 3. A pharmaceutical compositionthat comprises a compound according to claim 1 and a pharmaceuticallyacceptable carrier.
 4. A method of treating a bacterial infectioncomprising administering to a mammal in need of such treatment anantibacterial effective amount of the compound of claim 1.